Avishay Spitzer, Simon Gritsch, Masashi Nomura, Alexander Jucht, Jerome Fortin, Ramya Raviram, Hannah R Weisman, L Nicolas Gonzalez Castro, Nicholas Druck, Rony Chanoch-Myers, John J Y Lee, Ravindra Mylvaganam, Rachel Lee Servis, Jeremy Man Fung, Christine K Lee, Hiroaki Nagashima, Julie J Miller, Isabel Arrillaga-Romany, David N Louis, Hiroaki Wakimoto, Will Pisano, Patrick Y Wen, Tak W Mak, Marc Sanson, Mehdi Touat, Dan A Landau, Keith L Ligon, Daniel P Cahill, Mario L Suvà, Itay Tirosh
A subset of patients with IDH-mutant glioma respond to inhibitors of mutant IDH (IDHi), yet the molecular underpinnings of such responses are not understood. Here, we profiled by single-cell or single-nucleus RNA-sequencing three IDH-mutant oligodendrogliomas from patients who derived clinical benefit from IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation. We further integrate our findings with analysis of single-cell and bulk transcriptomes from independent cohorts and experimental models...
April 2, 2024: Cancer Cell
Ningning Niu, Xuqing Shen, Zheng Wang, Yueyue Chen, Yawen Weng, Feier Yu, Yingying Tang, Ping Lu, Mingzhu Liu, Liwei Wang, Yongwei Sun, Minwei Yang, Baiyong Shen, Jiabin Jin, Zipeng Lu, Kuirong Jiang, Yufeng Shi, Jing Xue
The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of cancer-associated fibroblasts (CAFs) as part of the host response to tumor cells. The origins and functions of transcriptionally diverse CAF populations in PDAC remain poorly understood. Tumor cell-intrinsic genetic mutations and epigenetic dysregulation may reshape the TME; however, their impacts on CAF heterogeneity remain elusive. SETD2, a histone H3K36 trimethyl-transferase, functions as a tumor suppressor...
March 31, 2024: Cancer Cell
Mingyang Liu, Yu Ren, Zhijun Zhou, Jingxuan Yang, Xiuhui Shi, Yang Cai, Alex X Arreola, Wenyi Luo, Kar-Ming Fung, Chao Xu, Ryan D Nipp, Michael S Bronze, Lei Zheng, Yi-Ping Li, Courtney W Houchen, Yuqing Zhang, Min Li
With limited treatment options, cachexia remains a major challenge for patients with cancer. Characterizing the interplay between tumor cells and the immune microenvironment may help identify potential therapeutic targets for cancer cachexia. Herein, we investigate the critical role of macrophages in potentiating pancreatic cancer induced muscle wasting via promoting TWEAK (TNF-like weak inducer of apoptosis) secretion from the tumor. Specifically, depletion of macrophages reverses muscle degradation induced by tumor cells...
March 29, 2024: Cancer Cell
Skylar A Giacobetti, Howard A Fine
In this issue of Cancer Cell, Spitzer and colleagues demonstrate the role of IDH inhibitors on IDHmutant gliomas in reducing proliferation and enhancing cell differentiation toward an astrocytic-like state, thus altering neurodevelopmental pathways. Despite clinical promise, unresolved questions regarding mechanisms of action and resistance underline the need for further research for treatment optimization.
March 29, 2024: Cancer Cell
Lukas Kraehenbuehl, Jedd D Wolchok, Taha Merghoub, Daniel Hirschhorn
Combined immune checkpoint blockade (ICB) for cancer exhibits good efficacy in a subset of patients but also associates with immune-related adverse events. Xue et al. use an elegant drug screening strategy to identify the antimicrobial drug clofazimine as an agent that both potentiates ICB efficacy and decreases immune-related adverse events.
March 25, 2024: Cancer Cell
Renée Maria Saliby, Chris Labaki, Tejas R Jammihal, Wanling Xie, Maxine Sun, Valisha Shah, Eddy Saad, M Harry Kane, Soki Kashima, Katherine Sadak, Talal El Zarif, Deepak Poduval, Robert J Motzer, Thomas Powles, Brian I Rini, Laurence Albiges, Sumanta K Pal, Bradley A McGregor, Rana R McKay, Sabina Signoretti, Eliezer M Van Allen, Sachet A Shukla, Toni K Choueiri, David A Braun
Saliby et al. show that a machine learning approach can accurately classify clear cell renal cell carcinoma (RCC) into distinct molecular subtypes using transcriptomic data. When applied to tumors biospecimens from the JAVELIN Renal 101 (JR101) trial, a benefit is observed with immune checkpoint inhibitor (ICI)-based therapy across all molecular subtypes.
March 22, 2024: Cancer Cell
Gang Xue, Xin Li, Muhammad Kalim, Jing Fang, Zhiwu Jiang, Ningbo Zheng, Ziyu Wang, Xiaoyin Li, Maen Abdelrahim, Zhiheng He, Mikhail Nikiforov, Guangxu Jin, Yong Lu
Emerging as the most potent and durable combinational immunotherapy, dual anti-PD-1 and CTLA-4 immune checkpoint blockade (ICB) therapy notoriously increases grade 3-5 immune-related adverse events (irAEs) in patients. Accordingly, attempts to improve the antitumor potency of anti-PD-1+CTLA-4 ICB by including additional therapeutics have been largely discouraged due to concerns of further increasing fatal toxicity. Here, we screened ∼3,000 Food and Drug Administration (FDA)-approved drugs and identified clofazimine as a potential third agent to optimize anti-PD-1+CTLA-4 ICB...
March 19, 2024: Cancer Cell
Pierluigi Di Chiaro, Lucia Nacci, Fabiana Arco, Stefania Brandini, Sara Polletti, Andrea Palamidessi, Benedetta Donati, Chiara Soriani, Francesco Gualdrini, Gianmaria Frigè, Luca Mazzarella, Alessia Ciarrocchi, Alessandro Zerbi, Paola Spaggiari, Giorgio Scita, Simona Rodighiero, Iros Barozzi, Giuseppe R Diaferia, Gioacchino Natoli
Intratumor morphological heterogeneity of pancreatic ductal adenocarcinoma (PDAC) predicts clinical outcomes but is only partially understood at the molecular level. To elucidate the gene expression programs underpinning intratumor morphological variation in PDAC, we investigated and deconvoluted at single cell level the molecular profiles of histologically distinct clusters of PDAC cells. We identified three major morphological and functional variants that co-exist in varying proportions in all PDACs, display limited genetic diversity, and are associated with a distinct organization of the extracellular matrix: a glandular variant with classical ductal features; a transitional variant displaying abortive ductal structures and mixed endodermal and myofibroblast-like gene expression; and a poorly differentiated variant lacking ductal features and basement membrane, and showing neuronal lineage priming...
March 18, 2024: Cancer Cell
Chun-Pu Lin, Pierre L Levy, Astrid Alflen, Georgi Apriamashvili, Maarten A Ligtenberg, David W Vredevoogd, Onno B Bleijerveld, Ferhat Alkan, Yuval Malka, Liesbeth Hoekman, Ettai Markovits, Austin George, Joleen J H Traets, Oscar Krijgsman, Alex van Vliet, Joanna Poźniak, Carlos Ariel Pulido-Vicuña, Beaunelle de Bruijn, Susan E van Hal-van Veen, Julia Boshuizen, Pim W van der Helm, Judit Díaz-Gómez, Hamdy Warda, Leonie M Behrens, Paula Mardesic, Bilal Dehni, Nils L Visser, Jean-Christophe Marine, Gal Markel, William J Faller, Maarten Altelaar, Reuven Agami, Michal J Besser, Daniel S Peeper
Genes limiting T cell antitumor activity may serve as therapeutic targets. It has not been systematically studied whether there are regulators that uniquely or broadly contribute to T cell fitness. We perform genome-scale CRISPR-Cas9 knockout screens in primary CD8 T cells to uncover genes negatively impacting fitness upon three modes of stimulation: (1) intense, triggering activation-induced cell death (AICD); (2) acute, triggering expansion; (3) chronic, causing dysfunction. Besides established regulators, we uncover genes controlling T cell fitness either specifically or commonly upon differential stimulation...
March 13, 2024: Cancer Cell
Darko Barisic, Christopher R Chin, Cem Meydan, Matt Teater, Ioanna Tsialta, Coraline Mlynarczyk, Amy Chadburn, Xuehai Wang, Margot Sarkozy, Min Xia, Sandra E Carson, Santo Raggiri, Sonia Debek, Benedikt Pelzer, Ceyda Durmaz, Qing Deng, Priya Lakra, Martin Rivas, Christian Steidl, David W Scott, Andrew P Weng, Christopher E Mason, Michael R Green, Ari Melnick
ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. We show that ARID1A orchestrates B cell fate during the germinal center (GC) response, facilitating cooperative and sequential binding of PU.1 and NF-kB at crucial genes for cytokine and CD40 signaling. The absence of ARID1A tilts GC cell fate toward immature IgM+ CD80- PD-L2- memory B cells, known for their potential to re-enter new GCs. When combined with BCL2 oncogene, ARID1A haploinsufficiency hastens the progression of aggressive follicular lymphomas (FLs) in mice...
March 7, 2024: Cancer Cell
Benjamin Wolf, Rakesh K Jain
Tumor invasion into the lymphatic vasculature represents a critical step during malignant progression of epithelial cancers. In this issue of Cancer Cell, Zheng et al. unravel how cancer-associated fibroblasts interact with lymphatic endothelial cells and the extracellular matrix to promote lymphatic tumor invasion and suggest that these processes could be treatment targets.
March 6, 2024: Cancer Cell
Qing Deng, Priya Lakra, Panhong Gou, Haopeng Yang, Cem Meydan, Matthew Teater, Christopher Chin, Wenchao Zhang, Tommy Dinh, Usama Hussein, Xubin Li, Estela Rojas, Weiguang Liu, Patrick K Reville, Atish Kizhakeyil, Darko Barisic, Sydney Parsons, Ashley Wilson, Jared Henderson, Brooks Scull, Channabasavaiah Gurumurthy, Francisco Vega, Amy Chadburn, Branko Cuglievan, Nader Kim El-Mallawany, Carl Allen, Christopher Mason, Ari Melnick, Michael R Green
SMARCA4 encodes one of two mutually exclusive ATPase subunits in the BRG/BRM associated factor (BAF) complex that is recruited by transcription factors (TFs) to drive chromatin accessibility and transcriptional activation. SMARCA4 is among the most recurrently mutated genes in human cancer, including ∼30% of germinal center (GC)-derived Burkitt lymphomas. In mice, GC-specific Smarca4 haploinsufficiency cooperated with MYC over-expression to drive lymphomagenesis. Furthermore, monoallelic Smarca4 deletion drove GC hyperplasia with centroblast polarization via significantly increased rates of centrocyte recycling to the dark zone...
March 1, 2024: Cancer Cell
Manuel Colucci, Sara Zumerle, Silvia Bressan, Federico Gianfanti, Martina Troiani, Aurora Valdata, Mariantonietta D'Ambrosio, Emiliano Pasquini, Angelica Varesi, Francesca Cogo, Simone Mosole, Cristina Dongilli, Maria Andrea Desbats, Liliana Contu, Ajinkya Revankdar, Jingjing Chen, Madhuri Kalathur, Maria Luna Perciato, Rossella Basilotta, Laczko Endre, Stefan Schauer, Alaa Othman, Ilaria Guccini, Miriam Saponaro, Luisa Maraccani, Nicolò Bancaro, Ping Lai, Lei Liu, Nicolò Pernigoni, Federico Mele, Sara Merler, Lloyd C Trotman, Greta Guarda, Bianca Calì, Monica Montopoli, Andrea Alimonti
Cellular senescence can exert dual effects in tumors, either suppressing or promoting tumor progression. The senescence-associated secretory phenotype (SASP), released by senescent cells, plays a crucial role in this dichotomy. Consequently, the clinical challenge lies in developing therapies that safely enhance senescence in cancer, favoring tumor-suppressive SASP factors over tumor-promoting ones. Here, we identify the retinoic-acid-receptor (RAR) agonist adapalene as an effective pro-senescence compound in prostate cancer (PCa)...
February 27, 2024: Cancer Cell
Hanhao Zheng, Mingjie An, Yuming Luo, Xiayao Diao, Wenlong Zhong, Mingrui Pang, Yan Lin, Jiancheng Chen, Yuanlong Li, Yao Kong, Yue Zhao, Yina Yin, Le Ai, Jian Huang, Changhao Chen, Tianxin Lin
Cancer-associated fibroblasts (CAFs) exhibit considerable heterogeneity in advanced cancers; however, the functional annotation and mechanism of CAFs in early-stage cancers remain elusive. Utilizing single-cell RNA sequencing and spatial transcriptomic, we identify a previously unknown PDGFRα+ ITGA11+ CAF subset in early-stage bladder cancer (BCa). Multicenter clinical analysis of a 910-case cohort confirms that PDGFRα+ ITGA11+ CAFs are associated with lymphovascular invasion (LVI) and poor prognosis in early-stage BCa...
February 23, 2024: Cancer Cell
Quinlan Sievers, Omar Abdel-Wahab
The mSWI/SNF subunits ARID1A and SMARCA4 are mutated in B cell lymphomas. Now, Barisic et al. and Deng et al. find that loss of ARID1A or SMARCA4 contributes to lymphomagenesis by causing B cells to aberrantly re-enter germinal centers where they undergo repeated rounds of proliferation and somatic hypermutation.
February 20, 2024: Cancer Cell
Xinyuan Tong, Ayushi S Patel, Eejung Kim, Hongjun Li, Yueqing Chen, Shuai Li, Shengwu Liu, Julien Dilly, Kevin S Kapner, Ningxia Zhang, Yun Xue, Laura Hover, Suman Mukhopadhyay, Fiona Sherman, Khrystyna Myndzar, Priyanka Sahu, Yijun Gao, Fei Li, Fuming Li, Zhaoyuan Fang, Yujuan Jin, Juntao Gao, Minglei Shi, Satrajit Sinha, Luonan Chen, Yang Chen, Thian Kheoh, Wenjing Yang, Itai Yanai, Andre L Moreira, Vamsidhar Velcheti, Benjamin G Neel, Liang Hu, James G Christensen, Peter Olson, Dong Gao, Michael Q Zhang, Andrew J Aguirre, Kwok-Kin Wong, Hongbin Ji
KRASG12C inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRASG12C -mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRASG12C and STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRASG12C and KrasG12D lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition...
February 20, 2024: Cancer Cell
Shasha Chen, Beicheng Sun, Zhongjun Dong
Inducing senescence in tumor cells can stimulate anti-tumor immune responses. In this issue of Cancer Cell, Colucci et al. demonstrate that the combination of the RAR agonist Adapalene with the chemotherapy drug Docetaxel enhances tumor-suppressing senescence and activates an anti-tumor immune response through natural killer cells.
February 16, 2024: Cancer Cell
Michael Dennis, Robert Haddad
Advances in imaging and novel treatment approaches might have outpaced the prognostic capabilities of the current AJCC/UICC TNM 8th edition for staging nasopharyngeal carcinoma (NPC). In this issue of Cancer Cell, Du et al. propose a new TNM-9 classification that incorporates these updates.
March 11, 2024: Cancer Cell
Shujun Xiao, Fangfang Shi, Huaxin Song, Jingyi Cui, Derun Zheng, Hesong Zhang, Kai Tan, Jiaqi Wu, Xueqin Chen, Jiale Wu, Yigang Tang, Yuting Dai, Min Lu
Dozens of compounds that rescue tumor-associated mutant p53 have been reported. Xiao et al. perform 10 assays to evaluate effectiveness of the mutant p53-rescue compounds side-by-side but do not detect reliable rescue in any assay for the evaluated compounds, except for ATO and its analog PAT.
March 11, 2024: Cancer Cell
Darko Barisic, Christopher R Chin, Cem Meydan, Matt Teater, Ioanna Tsialta, Coraline Mlynarczyk, Amy Chadburn, Xuehai Wang, Margot Sarkozy, Min Xia, Sandra E Carson, Santo Raggiri, Sonia Debek, Benedikt Pelzer, Ceyda Durmaz, Qing Deng, Priya Lakra, Martin Rivas, Christian Steidl, David W Scott, Andrew P Weng, Christopher E Mason, Michael R Green, Ari Melnick
No abstract text is available yet for this article.
April 8, 2024: Cancer Cell
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